The present invention relates to the preparation of sodium diclofenac enteric-coated microcapsules, in particular, the preparation method by spray drying technique with methacrylic acid-ethyl acrylate copolymers (Eudragit L 30D) as the enteric-coating material. The spray-dried powder was mixed with a mixture of microcrystalline cellulose (neocel) to pregelatinized starch (flo-starch) and was directly compressed into a tablet.
Generally, sodium diclofenac is a widely used nonsteroidal anti-inflammatory drug to treat rheumatoid arthritis,.osteoarthritis and ankylosing spondylitis. This has been disclosed in the following references, "J. R. Caldwell, Am. J. Med., 80, (Suppl. 4B), 43-46(1986), R. Altman, Am. J. Med., 80, (Suppl. 4B), 48-52 (1986), J. J. Calabro, Am. J. Med., 80, (Suppl. 4B), 58-63 (1986), and R. N. Brogden, R. C. Heel, G. E. Pakes, T. M. Speight and G. S. Avery, Drugs, 20, 24-48 (1984)". In order to eliminate its gastro-intestinal (GI) effect, the main adverse effect for patients after taking diclofenac, (which has been disclosed in the following references, "W. M. O'brien, Am. J. Med., 80, (Suppl. 4B), 70-80 (1986), R. E. Small, Clin. Pharm., 8, 545-558 (1989)"), effective enteric-coated products have been developed and commercialized. They may allow a drug dosage form to pass through the acid environment of the stomach, then to disintegrate immediately in the upper intestine, releasing the drug. Numerous studies have been conducted to differentiate the multiple units from the single unit of enteric-coated preparations and have been disclosed in the references, "H. Maekawa, Y. Takagishi, K. Iwamoto, Y. Doi, T. Ogura, M. Ito, K. Kitamura and H. Fujimoto, Jap. J. Antibiot., 30, 631-638 (1977), M. Nakano, M. Itoh, J. Kazuhiko, H. Sekikawa and T. Arita, Int. J. Pharm., 4, 291-298 (1980), J. P. Dechesne, Int. J. Pharm., 37, 203-209 (1982)". There are many advantages for the multiple units of enteric-coated products as compared with the single unit of enteric dosage forms. For example, the multiple units may distribute well over a large surface area, thus minimizing the risk of local damage or erosion as caused by the dumping effect of the single unit. Compared with the single unit, they are also less variable and less dependent on gastric transit time. They may attain more constant plasma levels, achieving a slow-release effect, giving a higher accuracy in reproducibility dose by dose, and causing less decrease of bioavailability. This have been disclosed in the following references, "H. Bechgaard, Pharm. Acta Helv., 28, 149-157 (1982), C. Eskilson, Manuf. Chemist, 56, (3) 33-36 (1985), J. P. Dechesne and L. Dellattre, Int. J. Pharm., 34, 259-262 (1987), and M. J. Story, J. Pharm. Sci., 66, 1495-1496 (1977)". In particular, a single unit of enteric-coated product may be significantly influenced by the physiological pH condition of the patients and the existing foods, leading to poor bioavailability due to the change of disintegration time, which has been disclosed in the following references, "E. Nelson, Clin. Pharm. Ther., 4, 283-292 (1963), H. Maekawa, Y. Takagishi, Y. Doi and K. Iwamoto, Yakuzaigaku, 30, 94-99 (1970), G. T. Luce, Manuf. Chemist, 49, (7) 50-52, 67 (1978)". Therefore, the microdispersed or multiple-unit enteric-coated products were recently developed, which is well-known from references "J. P. Dechesne, Int. J. Pharm., 37, 203-209 (1982), C. Eskilson, Manuf. Chemist, 56, (3) 33-36 (1985), J. P. Dechesne and L. Dellattre, Int. J. Pharm., 34, 259-262 (1987), and C. D. Herzfeldt, A. Zimmer and R. Brehm, Pharm. Ind., 49, 948-951 (1987)". A spray drying aqueous formulation to prepare the enteric-coated microcapsules has been disclosed in the reference "H. Takenaka, Y. Kawashima and S. Y. Lin, J. Pharm. Sci., 69, 948-951 (1980)". Moreover, some interactions between the enteric-coating material and the drug during spray drying have been found, but it would not occur if wet granulation was used to prepare enteric-coated granules. This has been disclosed in the references "H. Takenaka, Y. Kawashima and S. Y. Lin, J. Pharm. Sci., 70, 1256-1260 (1981), and S. Y. Lin and Y. Kawashima, Pharm. Res., 4, 70-74 (1987)."
Recently, an aqueous polymeric latex or pseudolatex as enteric-coating material has been used for coating, to replace the organic solvent system, which has been disclosed in the references, "A. M. Mehta, M. J. Valazza and S. E. Abele, Pharm. Technol., 10, 46, 48-51, 53, 55-56 (1986), F. Gumowski, E. Doelker and R. Gurny, Pharm. Technol., 11, (2) 26-32 (1987)". Although the latter system offers some processing advantages such as low heat of vaporization, stability of water soluble or moisture-sensitive drugs and short processing time, safety precaution, environmental pollution and economic advantages have made the use of water more attractive and convenient when it was used as a solvent. The aqueous polymers often used for enteric coating are methacrylic acid-ethyl acrylate copolymers (Eudragit L 30D ), cellulose acetate phthalate (Aquateric) and polyvinyl acetate phthalate (Coateric), which has been disclosed in the reference "K. S. Murthy, N. A. Enders, M. Mahjour and M. B. Fawzi, Pharm. Technol., 10, (10) 36-46 (1986)". These aqueous polymers are insoluble in acidic media, but dissolve rapidly when the coating material is in contact with neutral or weak alkaline solution. Because water has a higher heat of vaporization, the appropriate equipment must be selected to offer a good drying efficiency. Fluid-bed dryer and coating pan are more often used than spray dryer to coat tablets or pellets with aqueous polymeric system in preparing sustained-release or enteric-coated products.